PCH represents a group of clinically and genetically heterogeneous neurodegenerative disorders with prenatal onset [14]. PCH1 is characterized by cerebellar hypoplasia along with degeneration of the bulbar and spinal motor neurons, which is identical to spinal muscular atrophy (SMA). Initial reports of PCH1 described it as a fatal disorder in neonates, with symptoms such as polyhydramnios, congenital contractures, respiratory failure, and severe muscle weakness [15, 16]. However, subsequent studies illustrated that the ventral pons could be spared, and patients might survive till puberty, with broadening of the clinical and neuroradiological spectrum of PCH1 [17, 18].

At present, PCH1 is further classified into six subtypes (PCH1A-F) based on the underlying causative genes. Of them, four are associated with variants in exosome genes: PCH1B is caused by EXOSC3 [6], PCH1C by EXOSC8 [7], PCH1D by EXOSC9 [8], and PCH1F by EXOSC1 [9]. On the other hand, PCH1A and PCH1E are caused by variants in VRK1 and SLC25A46 genes, respectively [19, 20].

PCH type 1C is an ultra-rare subtype of PCH, with only four reported families [7, 13]. The initial report by Boczonadi and co-authors [7] described three unrelated consanguineous families, two of them were of Hungarian Romanian origin who shared the same missense variant (c.815 G > C, p.Ser272Thr). The third family was of Palestinian descent and had a different missense variant (c.5 C > T, p.Ala2Val). Subsequently, in 2021 Rodríguez-García and coauthors [13] reported a Spanish family with three heterozygous EXOSC8 variants including the same missense variant found in the Hungarian Romanian families (Table 1).

Family 1 of Boczonadi et al. [7] comprised 7 patients, who all died with respiratory failure before reaching their second year. Similarly, one of the two sibs of Family 2, with the same variant, died at the age of 13 months while the other sib was alive at the time of publishing their study (9 months). The two sibs of Family 3 harboring the c.5 C > T (p.Ala2Val) variant showed a longer survival as one died at the age of 28 months while the other was alive (5 years). This led Boczonadi and co-authors [7] to consider PCH type 1C as a lethal type of PCH. Diversely, Rodríguez-García et al. [13] reported a 16-year-old boy with compound heterozygous variants in EXOSC8 and a slowly progressive milder phenotype. Our patient was 3 years and 4 months old at his last examination that pointed to better longevity in comparison to most of the reported cases.

Almost all described patients with EXOSC8 variants including ours (n = 13) exhibited psychomotor retardation, spasticity, SMA, and respiratory problems. The respiratory issues are likely caused by deficiencies in the respiratory chain complexes resulting in symptoms such as recurrent chest infections, tachypnea, abnormal breathing patterns which could eventually lead to respiratory failure [7, 13]. Spasticity was noted in 11/13 patients and was affecting both upper and lower limbs except for one patient who had lower limbs spasticity [7]. Impairment of hearing and vision were detected in all patients with the p.Ser272Thr variant described by Boczonadi et al. [7]. In contrast, Family 3 of Boczonadi et al. [7], the single patient described by Rodríguez-García et al. [13], and our patient showed normal hearing and did not develop visual loss. Interestingly, eye examination of our patient showed nystagmus and congenital esotropia which were also present in the single patient described by Rodríguez-García and co-authors [13].

Facial dysmorphism does not appear to be a unique feature for patients with EXOSC8 as only three patients (3/12) had specific facial features without clear description of such features [7]. Our patient had characteristic facies including dolichocephaly, long face, hypertelorism, receded mandible, pointed chin, microstomia and low-set large protruded ears. Thoroughly investigation of the exome data of our patient didn’t show any related variants to the abnormal facial features. Therefore, we postulate that dysmorphic facies might be part of the phenotypic spectrum of EXOSC8-related PCH1.

Inguinal hernia was observed in three patients with PCH1C [7]. Interestingly, our patient exhibited a diaphragmatic hernia. Although there is no clear association yet between EXOSC8 genes and the development of hernias, it could be attributed to the weak abdominal wall due to the severe axial hypotonia. Other rare findings with EXOSC8 variants are feeding difficulties (5 patients), tremors (4 patients), contractures (4 patients), dysmetria (1 patient), dysdiadochokinesia (1 patient), brachycephaly (1 patient), and scoliosis (1 patient). The variability in symptoms observed among the reported cases strongly suggests that EXOSC8 is likely to affect multiple systems in the body, and additional research is needed to fully understand the underlying mechanisms and delineate the associated clinical manifestations.

The reported EXOSC8 patients displayed variabilities in their brain imaging such as cerebellar hypoplasia, pontine hypoplasia, cerebral atrophy and thinning of the corpus callosum [7, 13]. Our patient had severe cerebellar hypoplasia (mainly hemispheres), mild cortical atrophic changes and thin corpus callosum. In addition, he had dilated ventricle, hypoplastic temporal lobes, and thinning of the brain stem which were not reported before extending the neuro-radiological spectrum of the disorder. Of note, the hemispheric cerebellar involvement in our patient was much more pronounced in comparison to the published scans.

In this study, we identified a new missense EXOSC8 variant (c.238 G > A, p.Val80Ile) which was confirmed by studying mRNA of the patient to result in skipping of exon 5 and production of an early stop codon (p.Val80Phefs*39). Our new variant raises the total number of reported EXOSC8 variants to five including four missense and one splice site variant (c.390 + 1delG) (Fig. 2D). Interestingly, this splice variant caused exon 7 skipping and also resulted in early protein truncation (p.Ser116Lysfs*27).

In conclusion, we described a new family with PCH type 1C and identified a novel EXOSC8 missense variant that resulted in exon skipping. Although majority of the clinical findings of our patient were similar to the previously reported patients, new and unusual findings such as dysmorphic facies, nystagmus, congenital esotropia, contractures and diaphragmatic hernia were observed. In addition, brain MRI showed dilated ventricles, hypoplastic temporal lobes, and thinning of the brain stem, which were not detected before in patients with EXOSC8 variants. Therefore, we believe that our study refines and expands the phenotypic and mutational spectrum of PCH type 1C.